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1.
Toxins (Basel) ; 13(12)2021 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-34941722

RESUMO

Venoms of solitary wasps are utilized for prey capture (insects and spiders), paralyzing them with a stinger injection to be offered as food for their larvae. Thus, the identification and characterization of the components of solitary wasp venoms can have biotechnological application. In the present study, the venom components profile of a solitary scoliid wasp, Campsomeriella annulata annulata, was investigated through a comprehensive analysis using LC-MS and -MS/MS. Online mass fingerprinting revealed that the venom extract contains 138 components, and MS/MS analysis identified 44 complete sequences of the peptide components. The peptides are broadly divided into two classes: bradykinin-related peptides, and linear α-helical peptides. Among the components of the first class, the two main peptides, α-campsomerin (PRLRRLTGLSPLR) and ß-campsomerin (PRLRRLTGLSPLRAP), had their biological activities evaluated. Both peptides had no effects on metallopeptidases [human neprilysin (NEP) and angiotensin-converting enzyme (ACE)] and acetylcholinesterase (AChE), and had no cytotoxic effects. Studies with PC12 neuronal cells showed that only α-campsomerin was able to enhance cell viability, while ß-campsomerin had no effect. It is noteworthy that the only difference between the primary structures from these peptides is the presence of the AP extension at the C-terminus of ß-campsomerin, compared to α-campsomerin. Among the linear α-helical peptides, annulatin (ISEALKSIIVG-NH2) was evaluated for its biological activities. Annulatin showed histamine releasing activity from mast cells and low hemolytic activity, but no antimicrobial activities against all microbes tested were observed. Thus, in addition to providing unprecedented information on the whole components, the three peptides selected for the study suggest that molecules present in solitary scoliid wasp venoms may have interesting biological activities.


Assuntos
Proteínas de Insetos/química , Proteínas de Insetos/toxicidade , Células PC12/efeitos dos fármacos , Fenômenos Toxicológicos/efeitos dos fármacos , Venenos de Vespas/química , Venenos de Vespas/toxicidade , Animais , Japão , Ratos
2.
Pak J Biol Sci ; 24(10): 1040-1047, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34842373

RESUMO

<b>Background and Objective:</b> Effect of some compounds such as Plant extracts (Techno oil and Berna Star), natural origin compounds (Top-nine, Repcar and Chitosan 5%) and classical chemical pesticides (methomyl and lambda-cyhalothrin) were studied against the terrestrial snail <i>Massylaea vertmiculata</i> using the bait technique. Material and Methods: LC<sub>50</sub> of the each tested compound of natural compounds were estimated after 14 days of treatment, while LC<sub>50</sub> of pesticide were evaluated after 72 hrs of treatment. The impact of LC<sub>50 </sub>of each tested compound on some biochemical parameters, total protein content, alkaline phosphatase (ALP) and acid phosphatase (ACP) activity were determined 48 hrs post treatment. <b>Results:</b> The results revealed that the methomyl and lambda-cyhalothrin were the most effective compounds against test land snails, followed by Repcar, Top-nine and Techno oil, while Berna Star and Nema Ultra Chem come in the last rank. The pesticide compound methomyl was the most toxic one against the tested terrestrial snail species, while the Chitosan 5% was the least toxic one. The results showed that all tested compounds caused fluctuated effect whether increasing or decreasing on all the studies parameters such as total protein content, ALP and ACP activity as well. However, the Techno oil and the Berna Star caused sever decreasing on total protein content and ACP, followed by Top-nine, Repcar, Chitosan 5% (Nema Ultra Chem) and plant extracts. <b>Conclusion:</b> The both tested natural compounds and plant extracts recorded satisfying results compared with methomyl and lambda-cyhalothrin effect and that can be used in the pest controlling programs against terrestrial snails to reduce the environmental pollution.


Assuntos
Gastrópodes/metabolismo , Fenômenos Toxicológicos , Animais , Extratos Vegetais/efeitos adversos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
3.
Int J Mol Sci ; 22(22)2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34830013

RESUMO

Mercury ranks third on the U.S. Agency of Toxic Substances and Disease Registry priority list of hazardous substances, behind only arsenic and lead. We have undertaken uncovering the mechanisms underlying the developmental toxicity of methylmercury (MeHg), inorganic mercury (HgCl2), lead acetate (Pb), and sodium arsenite (As). To probe these differences, we used the Drosophila model, taking advantage of three developmental transitions-pupariation, metamorphosis, and eclosion-to differentiate potentially unique windows of toxicity. We elaborated dose response profiles for each individual metal administered in food and accounted for internal body burden, also extending analyses to evaluate combinatorial metal mixture effects. We observed all four metals producing larval lethality and delayed pupariation, with MeHg being most potent. Compared to other metals, MeHg's potency is caused by a higher body burden with respect to dose. MeHg uniquely caused dose-dependent failure in eclosion that was unexpectedly rescued by titrating in HgCl2. Our results highlight a unique developmental window and toxicokinetic properties where MeHg acts with specificity relative to HgCl2, Pb, and As. These findings will serve to refine future studies aimed at revealing tissue morphogenesis events and cell signaling pathways, potentially conserved in higher organisms, that selectively mediate MeHg toxicity and its antagonism by HgCl2.


Assuntos
Drosophila melanogaster/efeitos dos fármacos , Mercúrio/toxicidade , Metais/toxicidade , Compostos de Metilmercúrio/toxicidade , Animais , Arsenitos/toxicidade , Drosophila melanogaster/crescimento & desenvolvimento , Humanos , Larva/efeitos dos fármacos , Compostos Organometálicos/toxicidade , Isoformas de Proteínas/toxicidade , Compostos de Sódio/toxicidade , Fenômenos Toxicológicos
4.
Inhal Toxicol ; 33(4): 128-142, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33957849

RESUMO

OBJECTIVE: The objective of this study was the assessment of risks from inhalation exposure of Austrian smokers to cadmium through established toxicological approaches with emphasis on the exposure assessment component, which is challenging regarding the actual amount of metal that is inhaled and the simulation of the smoking pattern. MATERIALS AND METHODS: Exposure assessment comprised an estimation of the proportion of cadmium inhaled through smoking and actual occurrence data in tobacco products and survey smoking habits, which were integrated in alternative scenarios through a deterministic and a probabilistic Monte Carlo simulation method. Risks were characterized through the comparison of the exposure with health-based guidance values, as well as through the assessment of the excess lifetime cancer risk (ELCR), the non-cancer hazard quotient (NCHQ), and the margin of exposure (MOE). The strengths, the uncertainties, and the limitations of the different methodologies were discussed. RESULTS AND DISCUSSION: Upper exposures are close or exceed the Permitted Daily Exposure. Respiratory ELCRs are unacceptable compared to the benchmark range of 1.0E-06 to 1.0E-04. Renal and respiratory NCHQs exceed the target value of 1.0 by 3- to 17-fold. MOEs are not protective enough for cancer and non-cancer effects. The amount of cadmium that reaches the lung is a key source of uncertainty. CONCLUSION: Probabilistic estimates provide a refined capture of the actual inhalation exposure. Risk estimates and gender and age profiles are alarming, especially for young smokers. Application of toxicological approaches, combined with realistic assessment of the inhalation exposure levels, can support risk communication and management.


Assuntos
Cádmio/administração & dosagem , Simulação por Computador , Modelos Biológicos , Fumar Tabaco/efeitos adversos , Áustria , Humanos , Exposição por Inalação , Método de Monte Carlo , Medição de Risco , Fumantes , Fenômenos Toxicológicos
5.
Proc Natl Acad Sci U S A ; 118(18)2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33903247

RESUMO

Lanthanides are a series of critical elements widely used in multiple industries, such as optoelectronics and healthcare. Although initially considered to be of low toxicity, concerns have emerged during the last few decades over their impact on human health. The toxicological profile of these metals, however, has been incompletely characterized, with most studies to date solely focusing on one or two elements within the group. In the current study, we assessed potential toxicity mechanisms in the lanthanide series using a functional toxicogenomics approach in baker's yeast, which shares many cellular pathways and functions with humans. We screened the homozygous deletion pool of 4,291 Saccharomyces cerevisiae strains with the lanthanides and identified both common and unique functional effects of these metals. Three very different trends were observed within the lanthanide series, where deletions of certain proteins on membranes and organelles had no effect on the cellular response to early lanthanides while inducing yeast sensitivity and resistance to middle and late lanthanides, respectively. Vesicle-mediated transport (primarily endocytosis) was highlighted by both gene ontology and pathway enrichment analyses as one of the main functions disturbed by the majority of the metals. Protein-protein network analysis indicated that yeast response to lanthanides relied on proteins that participate in regulatory paths used for calcium (and other biologically relevant cations), and lanthanide toxicity included disruption of biosynthetic pathways by enzyme inhibition. Last, multiple genes and proteins identified in the network analysis have human orthologs, suggesting that those may also be targeted by lanthanides in humans.


Assuntos
Endocitose/efeitos dos fármacos , Elementos da Série dos Lantanídeos/toxicidade , Saccharomyces cerevisiae/efeitos dos fármacos , Fenômenos Toxicológicos/genética , Vias Biossintéticas/efeitos dos fármacos , Genoma Fúngico/efeitos dos fármacos , Humanos , Elementos da Série dos Lantanídeos/farmacologia , Saccharomyces cerevisiae/genética , Toxicogenética/tendências
6.
Molecules ; 26(4)2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33572099

RESUMO

Hovenia dulcis Thunberg is an herbal plant, belonging to the Rhamnaceae family, widespread in west Asia, USA, Australia and New Zealand, but still almost unknown in Western countries. H. dulcis has been described to possess several pharmacological properties, such as antidiabetic, anticancer, antioxidant, anti-inflammatory and hepatoprotective, especially in the hangover treatment, validating its use as an herbal remedy in the Chinese Traditional Medicine. These biological properties are related to a variety of secondary metabolites synthesized by the different plant parts. Root, bark and leaves are rich of dammarane-type triterpene saponins; dihydrokaempferol, quercetin, 3,3',5',5,7-pentahydroflavone and dihydromyricetin are flavonoids isolated from the seeds; fruits contain mainly dihydroflavonols, such as dihydromyricetin (or ampelopsin) and hovenodulinol, and flavonols such as myricetin and gallocatechin; alkaloids were found in root, barks (frangulanin) and seeds (perlolyrin), and organic acids (vanillic and ferulic) in hot water extract from seeds. Finally, peduncles have plenty of polysaccharides which justify the use as a food supplement. The aim of this work is to review the whole scientific production, with special focus on the last decade, in order to update phytochemistry, biological activities, nutritional properties, toxicological aspect and regulatory classification of H. dulcis extracts for its use in the European Union.


Assuntos
Suplementos Nutricionais/normas , Regulamentação Governamental , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Rhamnaceae/química , Animais , União Europeia , Humanos , Compostos Fitoquímicos/efeitos adversos , Extratos Vegetais/efeitos adversos , Fenômenos Toxicológicos
7.
Int J Mol Sci ; 22(1)2020 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-33375373

RESUMO

L-5-hydroxytryptophan (5-HTP) is both a drug and a natural component of some dietary supplements. 5-HTP is produced from tryptophan by tryptophan hydroxylase (TPH), which is present in two isoforms (TPH1 and TPH2). Decarboxylation of 5-HTP yields serotonin (5-hydroxytryptamine, 5-HT) that is further transformed to melatonin (N-acetyl-5-methoxytryptamine). 5-HTP plays a major role both in neurologic and metabolic diseases and its synthesis from tryptophan represents the limiting step in serotonin and melatonin biosynthesis. In this review, after an look at the main natural sources of 5-HTP, the chemical analysis and synthesis, biosynthesis and microbial production of 5-HTP by molecular engineering will be described. The physiological effects of 5-HTP are discussed in both animal studies and human clinical trials. The physiological role of 5-HTP in the treatment of depression, anxiety, panic, sleep disorders, obesity, myoclonus and serotonin syndrome are also discussed. 5-HTP toxicity and the occurrence of toxic impurities present in tryptophan and 5-HTP preparations are also discussed.


Assuntos
5-Hidroxitriptofano/análise , 5-Hidroxitriptofano/farmacologia , Transtornos Mentais/tratamento farmacológico , Obesidade/tratamento farmacológico , Síndrome da Serotonina/tratamento farmacológico , Transtornos do Sono-Vigília/tratamento farmacológico , Fenômenos Toxicológicos , Animais , Biotecnologia , Humanos , Transtornos Mentais/metabolismo , Transtornos Mentais/patologia , Obesidade/metabolismo , Obesidade/patologia , Síndrome da Serotonina/metabolismo , Síndrome da Serotonina/patologia , Transtornos do Sono-Vigília/metabolismo , Transtornos do Sono-Vigília/patologia
8.
PLoS One ; 15(8): e0237254, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32853204

RESUMO

Although many novel phase I designs have been developed in recent years, few studies have discussed how to incorporate external information into dose-finding designs. In this paper, we first propose a new method for developing a phase I design, Bayesian optimal interval design (BOIN)[Liu S et al. (2015), Yuan Y et al. (2016)], for formally incorporating historical information. An algorithm to automatically generate parameters for prior set-up is introduced. Second, we propose a method to relax the fixed boundaries of the BOIN design to be adaptive, such that the accumulative information can be used more appropriately. This modified design is called adaptive BOIN (aBOIN). Simulation studies to examine performances of the aBOIN design in small and large sample sizes revealed comparable performances for the aBOIN and original BOIN designs for small sample sizes. However, aBOIN outperformed BOIN in moderate sample sizes. Simulation results also showed that when historical trials are conducted in settings similar to those for the current trial, their performance can be significantly improved. This approach can be applied directly to pediatric cancer trials, since all phase I trials in children are followed by similar efficient adult trials in the current drug development paradigm. However, when information is weak, operating characteristics are compromised.


Assuntos
Ensaios Clínicos Fase I como Assunto , Desenvolvimento de Medicamentos , Adulto , Algoritmos , Antineoplásicos/uso terapêutico , Teorema de Bayes , Criança , Ensaios Clínicos Fase I como Assunto/métodos , Simulação por Computador , Desenvolvimento de Medicamentos/métodos , Humanos , Neoplasias/tratamento farmacológico , Projetos de Pesquisa , Tamanho da Amostra , Fenômenos Toxicológicos/efeitos dos fármacos
9.
Rev. baiana saúde pública ; 44(1): 41-54, 20200813.
Artigo em Português | LILACS | ID: biblio-1253108

RESUMO

Por produzir elevado impacto socioeconômico, promovendo custos e danos evitáveis, além de ter efeitos nocivos ao organismo humano, a intoxicação humana é considerada um problema importante em saúde pública. Com o envelhecimento, os indivíduos ficam suscetíveis a diversas doenças e agravos em saúde, e dentre eles, é importante notar-se os eventos toxicológicos ocorridos por várias circunstâncias, como o uso de polifarmácia, tentativa de suicídio, erro de prescrição médica, erro na administração do medicamento, entre outros, causas cada vez mais presente nessa população. Dessa forma, este artigo tem o objetivo de determinar o perfil e a tendência dos eventos toxicológicos ocorridos em idosos. Trata-se de estudo de tendência, realizado com indivíduos com 60 anos ou mais, notificados por um Centro de Informação e Assistência Toxicológica de Londrina (CIATox-Londrina), de 1985 a 2014. As variáveis foram coletadas através do banco de dados do CIATox-Londrina, e a análise de tendência realizada por meio de modelos de regressão linear simples. Identificou-se 2.042 casos de eventos toxicológicos em idosos, predominando a faixa etária de 60 a 69 anos (61,9%). A maioria (69,1%) foram casos de evento acidental, de forma aguda (98,2%), envolvendo animais (64,6%), pesticidas (16,5%) e medicamentos (10,8%) como principais agentes. Casos com animais apresentaram tendências de aumento significativas (R2 = 0,682; p = 0,03; ß1 = 1,542). Tal tendência também foi observada no sexo masculino (R2 = 0,766; p = 0,001; ß1 = 1,855). Observou-se predominância de eventos envolvendo animais, pesticidas e medicamentos, com tendência de aumento significativo em casos com animais, tanto em toda população avaliada como no sexo masculino.


Human intoxication is considered an important public health problem because it produces a high socioeconomic impact, promoting avoidable costs and damages, in addition to having harmful effects on the human body. With aging, individuals are susceptible to various diseases and health problems. Among several health problems, it is important to note the toxicological events that occurred due to various circumstances, such as polypharmacy, suicide attempt, wrong medical prescription, wrong medication administration, among others, causes increasingly present in this population. This study aims at determining the profile and trend of toxicological events among older adults. A trend study was conducted with individuals aged 60 years or older that were notified by a Center for Information and Toxicological Assistance of Londrina CIATox, from 1985 to 2014. Variables were obtained from the CIATox database. Trend analysis performed using simple linear regression models. In total, 2042 cases of toxicological events were identified, predominating from 60 to 69 years (61.9%). The events were mostly accidental (69.1%) and acute (98.2%), involving animals (64.6%), pesticides (16.5%) and drugs (10.8%) as main agents. Cases with animals showed significant increase tendencies (R2 = 0.682, p = 0.03, ß1 = 1.542). This trend was also observed in males (R2 = 0.766, p = 0.001, ß1 = 1.855). There was predominance of events involving animals, pesticides and drugs, with tendency to increase in cases with animals, both among the total population and among males.


Dado que la intoxicación humana produce un alto impacto socioeconómico, con costos y daños evitables, además de tener efectos nocivos sobre el cuerpo humano, se considera este trastorno un importante problema de salud pública. Con el envejecimiento, las personas son susceptibles a diversas enfermedades y problemas de salud; entre los cuales es importante tener en cuenta los eventos toxicológicos que ocurrieron debido a diversas circunstancias, como el uso de polifarmacia, intento de suicidio, error de prescripción médica, error en la administración de medicamentos, entre otros, causas cada vez más presentes en esta población. Este estudio tuvo como objetivo determinar el perfil y la tendencia de eventos toxicológicos que ocurrieron con los ancianos. Este es un estudio de tendencias, realizado con individuos de 60 años o más, notificados por un Centro de Información y Asistencia Toxicológica (CIATox) en Londrina, de 1985 a 2014. Las variables fueron recopiladas por la base de datos CIATox; y el análisis de tendencias se realizó con el uso de modelos de regresión lineal simple. Se identificaron 2.042 casos de eventos toxicológicos en ancianos, con una predominancia de edad de 60 a 69 años (61,9%). La mayoría (69,1%) fueron casos accidentales, agudos (98,2%), involucrando animales (64,6%), pesticidas (16,5%) y medicamentos (10,8%) como principales agentes. Los eventos con animales mostraron tendencias significativas al alza (R2 = 0,682; p = 0,03; ß1 = 1,542). Esta tendencia también se observó en varones (R2 = 0,766; p = 0,001; ß1 = 1,855). Hubo un predominio de eventos que involucraron animales, pesticidas y medicamentos, con una tendencia a un aumento significativo en los casos con animales, tanto en toda la población evaluada como en el sexo masculino.


Assuntos
Humanos , Intoxicação , Idoso , Saúde Pública , Fenômenos Toxicológicos
10.
JAMA Netw Open ; 3(7): e208516, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32687586

RESUMO

Importance: Synthetic cannabinoids (SCs), commonly known as K2, spice, or fake weed, are cheap, artificially manufactured recreational drugs that have emerged as a major public health threat in various regions of the US. Objective: To describe the clinical manifestations of SC intoxication. Design, Setting, and Participants: This case series assessed adults admitted to the intensive care unit from 2014 to 2016 with acute life-threatening complications of SC use. Data analysis was completed in October 2016. Exposures: Use of SCs such as K2, spice, or other synthetic versions of cannabinoids. Main Outcomes and Measures: Data collected included patient demographic data, medical history, presenting symptoms, physical findings, laboratory and imaging data, and intensive care unit and hospital course. Results: Thirty patients (mean age, 41 years [range, 21-59 years]; 24 men [80%]) with SC ingestion were admitted to the intensive care unit over a 2-year period. Thirteen patients were undomiciled. The majority had a history of polysubstance abuse, psychiatric illness, or personality disorder. The admission diagnoses were coma (10 patients [33%]), agitation (10 patients [33%]), and seizure (6 patients [20%]). Eighteen patients (60%) had acute respiratory failure, and tracheal intubation was required in 21 patients (70%) for either airway protection or acute respiratory failure. Rhabdomyolysis was noted in 8 patients (26%). A man developed transient cerebral edema with loss of gray-white differentiation but had complete recovery. A woman with history of asthma died of acute respiratory distress syndrome. All patients underwent routine toxicology testing, which was unrevealing in 16 cases and revealed coingestion in the remainder. Sixteen patients (53%) left the hospital against medical advice. Conclusions and Relevance: Ingestion of SCs can lead to life-threatening complications, including severe toxic encephalopathy, acute respiratory failure, and death. Synthetic cannabinoids are undetectable in routine serum and urine toxicology testing but can be suspected on the basis of history and clinical presentation, which may include extreme agitation or coma. Frontline clinicians must be aware of the presentation and be vigilant in suspecting SC intoxication.


Assuntos
Edema Encefálico , Canabinoides/toxicidade , Estado Terminal , Síndromes Neurotóxicas , Insuficiência Respiratória , Transtornos Relacionados ao Uso de Substâncias , Adulto , Edema Encefálico/etiologia , Edema Encefálico/terapia , Cuidados Críticos/métodos , Cuidados Críticos/estatística & dados numéricos , Estado Terminal/epidemiologia , Estado Terminal/terapia , Ingestão de Alimentos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Drogas Ilícitas/toxicidade , Masculino , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/terapia , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Detecção do Abuso de Substâncias/métodos , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/terapia , Fenômenos Toxicológicos , Resultado do Tratamento , Estados Unidos/epidemiologia
11.
Ned Tijdschr Geneeskd ; 1642020 04 02.
Artigo em Holandês | MEDLINE | ID: mdl-32392011

RESUMO

It is argued by the author that the addition of flavorings to e-cigarette devices presents a major uncertainty in the health risks of these nicotine delivery-systems. These flavorings have usually been tested only for oral uptake situations and not for e-cigarette devices in which unkown and possible hazardous combustion products can be formed. A similar uncertainty exist for the de novo formation of combustion products of humectants. Experimental studies have already indicated the possibility of adverse effects on the respiratory system. The now observed lung symptoms with e-cigarette users are there not unexpected from a toxicological point of view. The overall complexity of the mixture of combustion products clearly hampers an adequate toxicological risk assessment, which is further increased by the large variety of liquids and delivery devices on the market. The use if e-cigarette devices may very well be a toxicological box of Pandora.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Aromatizantes/toxicidade , Higroscópicos/toxicidade , Humanos , Fenômenos Toxicológicos
12.
Food Chem Toxicol ; 138: 111206, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32113950

RESUMO

Redox biology and toxicology are interrelated fields that have produced valuable evidence regarding the role and clinical significance of reactive species. These issues are analyzed herein by presenting 6 arguments, as follows: Argument 1: There is no direct connection of redox-related pathologies with specific reactive species; Argument 2: The measurement of reactive species concentration is a major challenge due to their very short half lives; Argument 3: There is an interplay between reactive species generation and fundamental biological processes, such as energy metabolism; Argument 4: Reactive species exert beneficial biological action; Argument 5: Reactive species follow the hormesis phenomenon; Argument 6: Oxidative modifications of redox-related molecules are not necessarily interpreted as oxidative damage. We conclude that reactive species do not seem to exert clinical significance, which means that they lack a measurable cause-effect relation with chronic diseases. Unpredictable results could, nevertheless, arise through novel experimental setups applied in the field of toxicology. These are related to the real-life exposure scenario via the regimen of long-term low-dose (far below NOAEL) exposure to mixtures of xenobiotics and can potentially offer perspectives in order to investigate in depth whether or not reactive species can be introduced as clinically significant redox biomarkers.


Assuntos
Espécies Reativas de Oxigênio , Fenômenos Toxicológicos , Doença Crônica , Hormese , Nível de Efeito Adverso não Observado , Oxirredução , Estresse Oxidativo , Testes de Toxicidade
13.
Zhongguo Yi Liao Qi Xie Za Zhi ; 43(4): 282-285, 2019 Jul 30.
Artigo em Chinês | MEDLINE | ID: mdl-31460722

RESUMO

The threshold of toxicological concern (TTC), a risk estimation method based on compound structurally-related toxicity data, has been widely used by many countries and regions for the safety risk assessment of food packaging materials and additives etc. Toxicological risk estimation is of importance in the biological evaluation of medical devices. Application of the TTC approach to leachable from medical devices may reduce or replace some unnecessary biocompatibility tests, but consideration should be taken for contact duration and route differences, which could affect the applicability of TTC. We herein focused on analyzing the eligibility of TTC for its further application in biological evaluation of medical devices.


Assuntos
Equipamentos e Provisões , Embalagem de Alimentos , Equipamentos e Provisões/normas , Embalagem de Alimentos/normas , Medição de Risco , Fenômenos Toxicológicos
14.
Biochem J ; 476(7): 1149-1158, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988136

RESUMO

Adverse drug reactions (ADRs) are the unintended side effects of drugs. They are categorised as either predictable or unpredictable drug-induced injury and may be exhibited after a single or prolonged exposure to one or multiple compounds. Historically, toxicology studies rely heavily on animal models to understand and characterise the toxicity of novel compounds. However, animal models are imperfect proxies for human toxicity and there have been several high-profile cases of failure of animal models to predict human toxicity e.g. fialuridine, TGN1412 which highlight the need for improved predictive models of human toxicity. As a result, stem cell-derived models are under investigation as potential models for toxicity during early stages of drug development. Stem cells retain the genotype of the individual from which they were derived, offering the opportunity to model the reproducibility of rare phenotypes in vitro Differentiated 2D stem cell cultures have been investigated as models of hepato- and cardiotoxicity. However, insufficient maturity, particularly in the case of hepatocyte-like cells, means that their widespread use is not currently a feasible method to tackle the complex issues of off-target and often unpredictable toxicity of novel compounds. This review discusses the current state of the art for modelling clinically relevant toxicities, e.g. cardio- and hepatotoxicity, alongside the emerging need for modelling gastrointestinal toxicity and seeks to address whether stem cell technologies are a potential solution to increase the accuracy of ADR predictivity in humans.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Células-Tronco/efeitos dos fármacos , Animais , Trato Gastrointestinal/efeitos dos fármacos , Coração/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Modelos Biológicos , Fenômenos Toxicológicos
15.
Mol Syst Biol ; 15(2): e8636, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30782979

RESUMO

The liver and kidney in mammals play central roles in protecting the organism from xenobiotics and are at high risk of xenobiotic-induced injury. Xenobiotic-induced tissue injury has been extensively studied from both classical histopathological and biochemical perspectives. Here, we introduce a machine-learning approach to analyze toxicological response. Unsupervised characterization of physiological and histological changes in a large toxicogenomic dataset revealed nine discrete toxin-induced disease states, some of which correspond to known pathology, but others were novel. Analysis of dynamics revealed transitions between disease states at constant toxin exposure, mostly toward decreased pathology, implying induction of tolerance. Tolerance correlated with induction of known xenobiotic defense genes and decrease of novel ferroptosis sensitivity biomarkers, suggesting ferroptosis as a druggable driver of tissue pathophysiology. Lastly, mechanism of body weight decrease, a known primary marker for xenobiotic toxicity, was investigated. Combined analysis of food consumption, body weight, and molecular biomarkers indicated that organ injury promotes cachexia by whole-body signaling through Gdf15 and Igf1, suggesting strategies for therapeutic intervention that may be broadly relevant to human disease.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Xenobióticos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Fator 15 de Diferenciação de Crescimento/genética , Humanos , Rim/patologia , Fígado/patologia , Transdução de Sinais/efeitos dos fármacos , Fenômenos Toxicológicos/genética , Aprendizado de Máquina não Supervisionado
16.
Cell Biol Int ; 43(4): 429-436, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30672061

RESUMO

In this study we provide new evidence that the columnar vesicles of the sea anemone Bunodosoma cangicum are toxic in vivo and contain at least two active polypeptides, a neurotoxic and an apoptosis inducing polypeptide. Here we show that it is also an effective inducer of apoptosis in vivo in the nematode Caenorhabditis elegans. In addition, the anemone peptides rapidly paralyze C. elegans, and set in motion a sequence of events that result in the complete dissolution of the internal organs in adult animals within 60 min. Nematodes that survive the toxin treatment exhibit a decreased reproductive capacity. Interestingly, adult animals appear to be much more susceptible to the effects of the toxins than larval stages, suggesting possible developmentally dependent targets of the toxins. Here we also provide chemical characterization of the compounds through chromatographic analysis and mass spectrometry. Gel filtration chromatography coupled with reverse phase HPLC shows that our partially purified extract contains at least two principle components. Additionally, MALDI-TOF mass spectrometry analysis of our extract shows three principal compounds at 814.6, 2914.1, and 4360.3 m/z plus three other minor components or fragments. Mass spectrometry analysis also indicates the presence of three disulfide bridges. Which is in agreement with other characterizations of anemone venoms.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Anêmonas-do-Mar/metabolismo , Anêmonas-do-Mar/fisiologia , Sequência de Aminoácidos , Animais , Apoptose/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Cromatografia em Gel/métodos , Cromatografia Líquida de Alta Pressão/métodos , Peptídeos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Fenômenos Toxicológicos/fisiologia
17.
Front Med ; 13(2): 277-284, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29845582

RESUMO

The development of new proton-pump inhibitors (PPIs) with less adverse effects by lowering the pKa values of nitrogen atoms in pyrimidine rings has been previously suggested by our group. In this work, we proposed that new PPIs should have the following features: (1) number of ring II = number of ring I + 1; (2) preferably five, six, or seven-membered heteroatomic ring for stability; and (3) 1 < pKa1 < 4. Six molecular scaffolds based on the aforementioned criteria were constructed, and R groups were extracted from compounds in extensive data sources. A virtual molecule dataset was established, and the pKa values of specific atoms on the molecules in the dataset were calculated to select the molecules with required pKa values. Drug-likeness screening was further conducted to obtain the candidates that significantly reduced the adverse effects of long-term PPI use. This study provided insights and tools for designing targeted molecules in silico that are suitable for practical applications.


Assuntos
Simulação por Computador , Desenho de Fármacos , Inibidores da Bomba de Prótons/toxicidade , Humanos , Fenômenos Toxicológicos
19.
J Mol Graph Model ; 85: 232-241, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30227368

RESUMO

For evaluating the environmental risk associated using carbon nanotubes (CNTs), a successful prediction is desired for the adsorption of organic compounds (OCs) by CNTs at different adsorbate concentrations. This is most often achieved through poly-parameter linear solvation energy relationships (LSERs) based on solvatochromic descriptors. This study examines the real predictivity of the existing LSERs for predicting the adsorption of OCs by single-walled CNTs (SWCNTs) while comparing it with that of the models developed in the present work using quantum-mechanical descriptors. The real predictivity of the quantum-mechanical models and existing LSERs is compared using state-of-the-art statistical procedures employing an external prediction set of compounds not used in the model development. The quantum-mechanically computed mean polarizability, but originating from the interactions between electrons of parallel spin, is found to play an essential role in the adsorption of OCs by SWCNTs. Besides the solvatochromic descriptors (McGowan volume and molar excess refractivity), the instantaneous inter-electronic interactions, captured through electron-correlation based quantum-mechanical descriptors, are found to significantly affect the adsorption at varying adsorbate concentration. The models developed using a combination of quantum-mechanical and solvatochromic descriptors are found to be quite reliable. The models proposed were further employed to predict the adsorption of agrochemicals such as insecticides, pesticides, herbicides, as well as adsorption of endocrine disruptors and biomolecules such as nucleobases and steroid hormones. These are predicted to be strongly adsorbed by SWCNTs with Progesterone and Guanine exhibiting maximal interaction with the SWCNTs among biomolecules. The quantum-mechanical descriptors proposed in this work can be used for the risk assessment of SWCNTs in systems where adsorption is the primary process.


Assuntos
Agroquímicos/química , Compostos Orgânicos/química , Teoria Quântica , Adsorção , Agroquímicos/farmacologia , Fenômenos Mecânicos , Modelos Teóricos , Nanotubos de Carbono/química , Compostos Orgânicos/farmacologia , Relação Quantitativa Estrutura-Atividade , Fenômenos Toxicológicos
20.
Toxicol Pathol ; 46(2): 224-246, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29471779

RESUMO

Lysosomes have a central role in cellular catabolism, trafficking, and processing of foreign particles. Accumulation of endogenous and exogenous materials in lysosomes represents a common finding in nonclinical toxicity studies. Histologically, these accumulations often lack distinctive features indicative of lysosomal or cellular dysfunction, making it difficult to consistently interpret and assign adverse dose levels. To help address this issue, the European Society of Toxicologic Pathology organized a workshop where representative types of lysosomal accumulation induced by pharmaceuticals and environmental chemicals were presented and discussed. The expert working group agreed that the diversity of lysosomal accumulations requires a case-by-case weight-of-evidence approach and outlined several factors to consider in the adversity assessment, including location and type of cell affected, lysosomal contents, severity of the accumulation, and related pathological effects as evidence of cellular or organ dysfunction. Lysosomal accumulations associated with cytotoxicity, inflammation, or fibrosis were generally considered to be adverse, while those found in isolation (without morphologic or functional consequences) were not. Workshop examples highlighted the importance of thoroughly characterizing the biological context of lysosomal effects, including mechanistic data and functional in vitro readouts if available. The information provided here should facilitate greater consistency and transparency in the interpretation of lysosomal effects.


Assuntos
Lisossomos/efeitos dos fármacos , Lisossomos/patologia , Fenômenos Toxicológicos , Animais
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